Abstract:
:Activated RAS/BRAF oncogenes induce cellular senescence as a tumor-suppressive barrier in early cancer development, at least in part, via an oncogene-evoked DNA damage response (DDR). In contrast, Myc activation-although producing a DDR as well-is known to primarily elicit an apoptotic countermeasure. Using the Emu-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor beta (TGF-beta) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-beta action, like genetic inactivation of the senescence-related histone methyltransferase Suv39h1, significantly accelerates Myc-driven tumor development via cancellation of cellular senescence. These findings, recapitulated in human aggressive B cell lymphomas, demonstrate that tumor-prompted stroma-derived signals may limit tumorigenesis by feedback senescence induction.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Reimann M,Lee S,Loddenkemper C,Dörr JR,Tabor V,Aichele P,Stein H,Dörken B,Jenuwein T,Schmitt CAdoi
10.1016/j.ccr.2009.12.043subject
Has Abstractpub_date
2010-03-16 00:00:00pages
262-72issue
3eissn
1535-6108issn
1878-3686pii
S1535-6108(10)00006-1journal_volume
17pub_type
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